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Development of a synthetic equivalent of
α,α-dicationic acetic acid leading to unnatural
Cite this: Org. Biomol. Chem., 2022,
20, 2282
amino acid derivatives via tetrafunctionalized
methanes†
Haruyasu Asahara, *a,b Atsushi Bonkohara,a Masaya Takagi,a Kento Iwai,
Akitaka Ito, a,c Kotaro Yoshioka,d Shinki Tani,d Kazuto Umezud andNagatoshi Nishiwaki *a,ca,cDiethyl mesoxalate (DEMO) exhibits high electrophilicity and accepts the nucleophilic addition of a lessnucleophilic acid amide to aﬀord N,O-hemiacetal. However, our research showed that elimination of theamide moiety proceeded more easily than dehydration upon treatment with a base. This problem wasovercome by reacting DEMO with an acid amide in the presence of acetic anhydride to eﬃciently obtain
N,O-acetal. Acetic acid was eliminated leading to the formation of N-acylimine in situ upon treatment
with the base. N-Acylimine is also electrophilic, accepting the second nucleophilic addition by pyrrole or
Received 25th December 2021,
Accepted 25th February 2022

indole to form α,α-disubstituted malonates. Subsequent hydrolysis followed by decarboxylation resulted

DOI: 10.1039/d1ob02482ein (α-indolyl-α-acylamino)acetic acid formation; homologs of tryptophan. Through this process, DEMO
serves as a synthetic equivalent of α,α-dicationic acetic acid to facilitate nucleophilic introduction of the

rsc.li/obc

two substituents.

Introduction
Malonic ester synthesis is an important tool for elaborate
organic synthesis. The acidic methylene group readily generates enolate, which reacts with up to two electrophiles, andsubsequent hydrolysis and decarboxylation lead to the formation of α,α-disubstituted acetic acids (Scheme 1, upper).1,2
Through this process, diethyl malonate serves as a synthetic
equivalent of α,α-dianionic acetic acid (Fig. 1, upper). In contrast, the central carbonyl carbon of DEMO (diethyl mesoxalate, diethyl oxomalonate, diethyl ketomalonate), one of thevicinal tricarbonyl compounds, is highly electrophilic andreacts with versatile nucleophiles to aﬀord hemiacetals (Fig. 2,aSchool of Environmental Science and Engineering, Kochi University of Technology,
Tosayamada, Kami, Kochi 782-8502, Japan.
E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jpbGraduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka 1-6,
Suita, Osaka 565-0871, Japanc
Research Center for Molecular Design, Kochi University of Technology, Tosayamada,Kami, Kochi 782-8502, Japand
Kumiai Chemical Industry Co. Ltd., Nakanogo, Fuji, Shizuoka 421-3306, Japan† Electronic supplementary information (ESI) available: Spectral data and copies
of NMR spectra of compounds 5–12 and 16, crystallographic data of 11j and16h, and computational study for 5. CCDC 2130060 and 2130061. For ESI andcrystallographic data in CIF or other electronic format see DOI: 10.1039/
d1ob02482e

2282 | Org. Biomol. Chem., 2022, 20, 2282–2292

path a).3,4 High electrophilicity facilitates the nucleophilic
addition of acid amide, which is considered a masked aminogroup but is not generally applied as a nucleophile.4 If

Scheme 1 Synthetic schemes of α,α-disubstituted acetic acids using
diethyl malonate (upper) and using DEMO (lower).

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Organic & Biomolecular ChemistryFig. 1 Synthetic equivalents of α,α-dianionic and α,α-dicationic acetic
acids.

Fig. 2 Synthetic equivalents of α,α-dianionic and α,α-dicationic acetic
acids.

α,α-disubstituted malonates can be prepared from DEMO bysuccessive nucleophilic reactions, α,α-disubstituted acetic acidcan be obtained upon hydrolysis followed by decarboxylation(Scheme 1, lower). In this process, two types of substituents are
introduced nucleophilically, indicating that DEMO acts as a synthetic equivalent of α,α-dicationic acetic acid (Fig. 1, lower).
Numerous organic reactions using DEMO have beenreported in the literature, and can be categorized into several
types (Fig. 2). In the reaction of DEMO with a dinucleophile, a
new ring is formed between the central carbon and the adjacent ester functionality in almost all cases ( path b).5 Double
addition to the central carbonyl group of DEMO, it is limited
to intramolecular ring closure ( path c);6 however, to the best of
our knowledge, the introduction of two substituents via successive double nucleophilic addition to the central carbon has
not been performed. The chemical conversion of hemiacetals
has been extensively studied. When reagents possess nucleophilic and electrophilic sites, the formed hemiacetal attacks
the electrophilic site of the nucleophile via dipolar cycloaddition ( path d).7 Conversely, dehydration of the hemiacetal
forms an electron-deficient double bond ( path e),8–10 which
subsequently accepts the addition of less nucleophilic
reagents, such as pyrrole.10
We focused on N-acylimines (Y = N, R = acyl), which canaccept nucleophilic addition to form α,α-disubstituted malonates. However, the synthesis of N-acylimines involves multistep reactions: nitrosoation at the α-position of malonate,11This journal is © The Royal Society of Chemistry 2022

Paper
reduction to an amino group,11 N-acylation, α-bromination12and dehydrobromination.12 Although N-acetylimine is directly
prepared from DEMO via the aza-Wittig reaction, theN-substituent is limited to an acetyl group.9 In our previous
work, we demonstrated that DEMO eﬃciently reacted with versatile acid amides to aﬀord the corresponding hemiacetals,4
which serves as precursors of N-acylimines modifiable by theacyl group upon dehydration.
Considering the above-mentioned background and our previous work,4,10 we planned a new synthetic strategy for unnatural amino acid derivatives using double nucleophilic
addition to DEMO. The high electrophilicity of DEMO allows
the attack of less nucleophilic acid amides, which facilitates
the introduction of protected amino groups in a single step.4
Dehydration of the obtained hemiacetals facilitates the formation of N-acylimines possessing versatile acyl groups, which
are subjected to reactions with second nucleophiles such as
pyrroles and indoles.10 Subsequent hydrolysis, followed by decarboxylation, leads to the formation of N-protected unnaturalamino acids.
Oligopeptides are widely used in medicinal chemistry;
however, the diversity of the resulting framework is limited
when natural amino acids are used as building blocks. Hence,the development of facile methods for the synthesis of unnatural amino acids has gained attention recently. Aminoacids are generally synthesized by connecting small molecules
via new bond formation (Fig. 3, methods a–c). Method a
involves the substitution of α-substituted α-bromoacetic acidwith ammonia or ammonium salt.13 Method b, the Strecker
reaction,14 provides amino acids by the addition of cyanide to
the α-substituted imine, followed by hydrolysis of the cyanogroup. In these cases, precursors possessing a substituent at
the α-position should be prepared beforehand, which is a significant disadvantage when constructing a compound library.
Reactions of masked amino acids (hydantoin) with aldehydes
or ketones (method c) facilitate the modification of the
α-substituents; however, it is necessary to use a strong baseand the subsequent hydrogenation limits usable substrates
possessing a functional group.15 A combination of methods b
and c, referred as the Bucherer–Bergs reaction, also furnishes

Fig. 3 Commonly used synthetic methods for α-substituted aminoacids.

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5,5-disubstituted hydantoins.16 In contrast, our synthetic
method (method d) achieved the synthesis of amino acidderivatives by decarboxylation17 of α,α-disubstituted malonate,in which the α-substituent is easily modified by altering thenucleophile. Because α,α-disubstituted malonate has multiple
coordination sites, control of stereochemistry is expected to beeasier than methods a–c.

Results and discussion
4-Methylbenzamide 1a (Scheme 1, R = 4-MeC6H4) was selected
as a model substrate for the first nucleophile. Upon heating at
60 °C for 18 h in acetonitrile, DEMO reacted with 1a to aﬀord
N,O-hemiacetal 2a with 92% yield. When 2a was subjected to
the reaction with the second nucleophile, pyrrole 3, under thesame conditions, no reaction proceeded, presumably due tothe congested structure and low electrophilicity of 2a. Thus,
the dehydration of 2a leading to N-acylimine 4a was studied.
Although microwave heating (at 140 °C) and treatment withacids (BF3·OEt2, H2SO4), bases (NEt3, K2CO3, tert-BuOK), or
molecular sieves 3 Å were attempted, the recovery of 2a or elimination of amide 1a yielding DEMO was observed without any
detectable 4a. The low reactivity of 2a was due to the reduced
elimination ability and high acidity of the hydroxy group. Thisdisadvantage was addressed by using the reaction between
DEMO and 1a in the presence of acetic anhydride. Although
the less nucleophilic 1a cannot attack acetic anhydride, theformed N,O-hemiacetal 2a can attack it by mooring the amide
functionality to aﬀord N,O-acetal 5a (Scheme 2). However, only
trace amounts of 5a were detected, which was due to the competitive hydration of DEMO leading to the formation of gemdiol (Table 1, entry 1). The addition of molecular sieves 3 Å
considerably increased the yield, and 5a was quantitatively
obtained when two equivalents of acetic anhydride were utilized (entries 2 and 3).
The preparative method was applied to other acid amides
1b–j (R = Ph 1b, C6F5 1c, Me 1d, Et 1e, Pr 1f, Me(CH2)10 1g,
tert-Bu 1h, CF3 1i, tert-BuO 1j) to quantitatively aﬀord thecorresponding N,O-acetals 5b–j, except for 5i (94% yield). It is

Scheme 2 Synthesis of N,O-acetal 5 by nucleophilic addition of amide
1 to DEMO in the presence of acetic anhydride.

2284 | Org. Biomol. Chem., 2022, 20, 2282–2292

Organic & Biomolecular Chemistry
Table 1

1
2
3

Optimization of reaction conditions for forming 5a

Ac2O/equiv.

Additive

Yield of 5a/%

1
1
2

—
Molecular sieves 3 Å
Molecular sieves 3 Å

472
Quant.

noteworthy that the reaction proceeded eﬃciently even in thecase of highly electron-deficient amides such as pentafluorobenzamide 1c and trifluoroacetamide 1i, and bulky pivalamide
1h. In addition, this protocol enabled the direct introductionof Boc-protected amino group by using urethane 1j.
Next, the formation of N-acylimine 4 was investigated(Scheme 3). When N,O-acetal 5a was treated with triethylamine
at room temperature in chloroform-d, acetic acid was easily
eliminated, leading to N-acylimine 4a in situ, which was confirmed by the 1H and 13C NMR spectra. Other N-acylimines, 4i
and 4j, were similarly obtained from 5i and 5j, respectively.
The generated N-acylimines 4 were subjected to a second
nucleophilic addition in one-pot without the isolation of 4
because they gradually hydrolyze leading to DEMO and amide
1. To a solution of N,O-acetal 5a in toluene, were added triethylamine and pyrrole 3, and the resulting mixture washeated at 50 °C for 1 d in a sealed tube to produce the double
adduct 6a with 26% yield (Table 2, entry 1). Elevating thetemperature and using 1.2 equiv. of 3 increased reaction
eﬃciency (entries 2–5). Among the solvents tested, toluene was
the most suitable (entries 6–8). Consequently, the reaction conditions in entry 4 were determined to be optimal.
In the series of reactions listed in Table 2, the reaction
mixture was washed with hydrochloric acid to remove thebase, during which adduct 6a was obtained without decomposition. Approximately half of the 6a decomposed to DEMO andamide 1a upon treatment with column chromatography on
silica gel. This was presumably because of the diﬀerence intime under acidic conditions. A plausible mechanism for thisphenomenon is shown in Scheme 3. After prototropy from
1-position to 2-position of the pyrrole ring, pyrrole 3 was eliminated to aﬀord DEMO and benzamide 1a via the hydrolysis of
the intermediately formed N-acylimine 4a (Scheme 4).

Scheme 3

Conversion of N,O-acetal 5 to N-acylimine 4.

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Table 2Paper

Optimization of reaction conditions for the synthesis of 6a

Entry

Solv.

Temp./°C

Time/hYielda/%

1
2
3
4
5b
6
7
8

TolueneTolueneTolueneTolueneToluene
CHCl3
THF
Acetonitrile

50
80
80
120
120
120
120
120

24
24
3
3
3
3
3
3

26
82
75
88
67
64
42
37

a

Table 3Synthesis of other double adducts 6–15 aDetermined by 1H NMR. b 1.0 equiv. of 3 was used.

Scheme 4 A plausible mechanism for the decomposition of double
adduct 6a.

The optimized conditions were applied to other N,O-acetals
5 and pyrroles/indoles (Table 3). Although double adducts
6–11 were purified by extraction or recrystallization, it was
sometimes diﬃcult, depending on the structure of the substrates 1 and pyrroles/indoles. Alkyl-substituted pyrroleseﬃciently underwent nucleophilic addition to 5a, leading to
adducts 7a–9a because of the high electron density on the
pyrrole ring. Indole (benzo[b]pyrrole) reacted with 5a to
produce adduct 10a, which was also unstable under acidic conditions. In this case, prototropy from the 1-position to the
3-position of the indole ring was a key step. Adducts 11a and12a obtained from the corresponding N-methylindoles,
respectively, were stable for purification by using column
chromatography on silica gel. Hence, other N-protectedindoles were employed; however, adducts 13a–15a were notdetected because of the electron-withdrawing properties andsteric hindrance of the N-substituent. N-Trifluoroacetyl and
N-Boc N,O-acetals 5i and 5j, respectively, exhibited similar reactivities to furnish the corresponding double adducts 6 and 11.
Surprisingly, the reaction of N-acetyl-N,O-acetal 5d with
N-methylindole resulted in only trace amounts of adduct 11d,This journal is © The Royal Society of Chemistry 2022a
A toluene solution of N,O-acetal 5 and pyrrole/indole (1.2 equiv.), andtriethylamine (1.5 equiv.) was heated at 120 °C for 3 h in a sealed tube.
The yields were determined by 1H NMR.

even though severe reaction conditions were utilized (Table 4,entry 1). When the reaction was monitored by 1H NMR, only asmall amount of N-acylimine 4d was detected, which indicatesthat the yield of 11d has a parallel relationship with theeﬃciency generation of 4d. Interestingly, the longer the alkyl
group, the higher the yield of 11 (entries 1–4), and the bulkinessof the alkyl group was found to increase the reactivity of N,Oacetal 5. N,O-Acetal 5h derived from pivalamide 1h exhibited considerably higher reactivity to aﬀord 11h with 57% yield (entry 5).
To gain insight into this steric eﬀect, DFT calculations wereconducted for 5d (R = Me), 5h (R = tert-Bu), and 5k (R = Bu);however, notable diﬀerences in bond lengths and bond angles
between them were not confirmed. Although no clear evidence
was obtained, one possible reason is as follows: when thebulky N-acyl group repels with ethoxycarbonyl groups, the N–H
and acetyl groups are closed together, which accelerates theelimination of acetic acid (Fig. 4).
The synthesized α,α-disubstituted malonates 11 were subjected to hydrolysis under various conditions. In the cases ofOrg. Biomol. Chem., 2022, 20, 2282–2292 | 2285

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Table 4 Eﬀect of the alkyl group of N,O-acetal 5 for the formation of 4
and for the second addition of N-methylindole leading to 11

Table 5

Hydrolysis of adduct 11 leading to α,α-disubstituted acetic acid 16

Substrate
Entry

R

1
2
3
4

Tol
tert-BuO
CF3
CF3

a

Entry

R

1
2
3
4
5

Me
Et
Pr
Undecbtert-Bu

a

d
e
f
g
h

Yield of 4 a/%

Yield of 11 a/%

0
5
12
8
42

2
11
23
21
57

11a
11j
11i
11i

Solv.

Time/hYielda/%
16

EtOH
EtOH
EtOH
MeCN

3
3
3
18

Quant.
80—b—b

Determined by 1H NMR. b Complex mixture.

Table 6

Hydrolysis and decarboxylation of double adducts 11

Determined by 1H NMR. b Undec: –(CH2)10CH3.

Fig. 4

Elimination of acetic acid leading to N-acylimine 4.

6a and 10a, all attempts failed because the presence of the N–
H group caused prototropy followed by elimination of the heteroaromatic moiety, as shown in Scheme 3. However, suchdecomposition was not observed for 11a derived fromN-methylindole. Hence, the reaction conditions were investigated using 11 (Table 5). When the double adduct 11a wastreated with sodium hydroxide in ethanol, hydrolysis and subsequent decarboxylation proceeded quantitatively to aﬀord
α,α-disubstituted acetic acid 16a (entry 1). Boc-substituted
adduct 11j also supplied only decarboxylated product 16j
without any detectable malonic acid (entry 2). In the case oftrifluoroacetyl adduct 11i, only a complex mixture wasobtained under both the reaction conditions (entries 3 and 4).
The reaction conditions were tested again using 11i, which
is more reactive than 11a and 11j. Several bases and solventswere evaluated, among which a combination of potassium tertbutoxide and THF was eﬀective for hydrolysis, followed by decarboxylation, leading to 16i with 87% yield (Table 6). In thisreaction, the water contained in THF acted as a source ofhydroxide. The yield considerably decreased when the same

2286 | Org. Biomol. Chem., 2022, 20, 2282–2292

a

Dry THF was used in an argon atmosphere.

reaction was conducted under the same conditions in an
argon atmosphere using dry THF as the solvent. Optimized
conditions were applied to the other adducts 11. Toluoyl-substituted adduct 11a was eﬃciently converted to 16a. Adducts
possessing a bulky acyl group, such as pivaloyl and tert-butoxycarbonyl (Boc) groups, underwent hydrolysis and decarboxylation to produce the corresponding α,α-disubstituted acetic
acids 16h and 16j, respectively. The α-amino acid derivatives
16 are homologs of tryptophan, which is expected to be usefulfor identifying new biologically active compounds.
This protocol facilitates modification of the acyl group byaltering amide 1. Synthesis of dipeptide was attempted using
this feature (Scheme 5). When DEMO was reacted with
L-prolineamide 1l in the presence of acetic anhydride, protection of not only the hydroxy group but also the ring nitrogenof the pyrrolidine was achieved. This is because amine canattack anhydride while amide cannot, by which doubly acetyl-This journal is © The Royal Society of Chemistry 2022

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Scheme 5

Paper

Synthesis of amino acid derivative 7Lf using prolineamide 1L.

ated N,O-acetal 5l was obtained with 88% yield. After the generation of N-acylimine 4l by triethylamine in situ, a second
nucleophilic addition by N-methylindole formed 11l with 75%
yield. Subsequent treatment with potassium tert-butoxide in
THF resulted in the hydrolysis of ester functions, followed bydecarboxylation, and resulted in the dipeptide 16l with 84%
yield. In the 1H NMR of 16l, signals of four kinds of isomers
were observed. When this compound was subjected to themeasurement of temperature-variable NMR spectra, each typeof signals coalesced (see ESI†). Hence, these isomers are notdiastereomers caused by two chiral centers but rotamers
caused by two amide functions.

Conclusions
A new approach for unnatural amino acid derivatives wasdemonstrated using DEMO. The high electrophilicity of DEMO
facilitates the acceptance of the double nucleophilic addition
via N-acylimine 4. In this protocol, an even less nucleophilicacid amide can be used as the first nucleophile, and pyrroles
and indoles 3 are used as the second nucleophile, which produced α,α-disubstituted malonates 6–12. Subsequent hydrolysis followed by decarboxylation furnished (α-indolylα-acylamino)acetic acids 11, which are homologs of tryptophan. Through this process, DEMO served as a synthetic equivalent of α,α-dicationic acetic acid to nucleophilically introduce two substituents. The application of this method byusing other nucleophiles is currently being studied, and theresults will be shown in subsequent papers.

Experimental section
GeneralAll reagents were purchased from commercial sources andused without further purification. Dry acetonitrile was alsoThis journal is © The Royal Society of Chemistry 2022

purchased from commercial source and used as received. 1H
and 13C NMR spectra were recorded on Bruker DPX-400 and
JEOL JMN-ECZ400S spectrometers (400 MHz and 100 MHz,
respectively) using TMS as an internal standard. The assignments of the 13C NMR were performed by DEPT experiments.
IR spectra were recorded on a JASCO FT/IR-4200 spectrometerequipped with an ATM detector. High-resolution mass spectra
were obtained on an AB SCEIX Triplet TOF 4600 mass spectrometer. Melting points were recorded on an SRS-Optimelt automated melting point system and were uncorrected. HPLC analysis was directly performed with chiral stationary phasecolumn, DAICEL CHIRALPAK or CHIRALCEL. Diﬀraction data
were collected at 93 K under a cold N2-gas stream on a Rigaku
XtaLAB Synergy-S/Mo system (λ = 0.71073 Å (Mo-Kα)). The integrated data were analyzed by using an Olex2 crystallographic
software package.18 The structures were solved with the ShelXT
structure solution program19 using Intrinsic Phasing andrefined with the ShelXL refinement package20 using the leastsquares minimization. Anisotropic refinement was performed
for all non-hydrogen atoms, and all the hydrogen atoms wereput at calculated positions.18–20 The geometrical optimization
was carried out for at the B3LYP/6-31 g(d,p) level of theory
implemented on Gaussian 09 package.21
General procedure for synthesis of N,O-acetal 5
To a solution of DEMO (0.87 g, 5.0 mmol) in toluene (20 mL),
4-methylbenzamide 1a (0.81 g, 6.0 mmol), molecular sieves 3A(1.7 g) and acetic anhydride (1.1 g, 10 mmol) were added, andthe resultant mixture was heated at 100 °C for 4 h. After filtration of molecular sieves, the filtrate was washed with water(30 mL × 2), dried over magnesium sulfate, and concentrated
in vacuo to aﬀord N,O-acetal 5a (1.36 g, 4.94 mmol, yield 99%)
as a white solid.
For the synthesis of other N,O-acetals 5b–j, the same experiments were conducted.
Diethyl α-acetoxy-α-[(4-methylbenzoyl)amino]malonate (5a).
Yield 99%. White solid, mp 121–122 °C. 1H NMR (400 MHz,

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CDCl3) δ 8.07 (1H, br s), 7.74 (2H, d, J = 8.0 Hz), 7.26 (2H, d, J =8.0 Hz), 4.33 (4H, q, J = 7.2 Hz), 2.41 (3H, s), 2.19 (3H, s), 1.28
(6H, t, J = 7.2 Hz); 13C NMR (101 MHz, CDCl3) δ 13.9 (CH3),
20.9 (CH3), 21.6 (CH3), 63.6 (CH2), 82.1 (C), 127.5 (CH), 129.4(CH), 143.3 (C), 163.7 (C), 165.9 (C), 170.2 (C), one signal forquaternary carbon was not observed presumably due to overlapping; IR (ATR, KBr) ν = 1679, 1758, 3427 cm−1; HRMS
(ESI-TOF) calcd for C17H21O7N [M + H]+ 352.1391; found352.1393.
Diethyl α-acetoxy-α-(benzoylamino)malonate (5b).4 Yield
quant. White solid, mp 50.5–51.2 °C; 1H NMR (400 MHz,CDCl3) δ 8.11 (1H, s), 7.84 (2H, d, J = 7.2 Hz), 7.56 (1H, t, J =7.2 Hz), 7.47 (2H, dd, J = 7.2, 7.2 Hz), 4.34 (4H, q, J = 7.2 Hz),2.20 (3H, s), 1.29 (6H, t, J = 7.2 Hz); 13C NMR (101 MHz,CDCl3) δ 13.9 (CH3), 20.9 (CH3), 63.7 (CH2), 82.1 (C), 127.5(CH), 128.8 (CH), 132.3 (C), 132.6 (CH), 163.6 (C), 165.9 (C),170.2 (C); IR (ATR) ν = 1672, 1744, 3318 cm−1; HRMS (ESI-TOF)
calcd for C16H19NNaO7 [M + Na]+: 360.1054; found 360.1059.
Diethylα-acetoxy-α-( pentafluorobenzoylamino)malonate(5c). Yield 99%. White solid, mp 131–132 °C; 1H NMR(400 MHz, CDCl3) δ 8.01 (1H, br s), 4.40–4.25 (4H, m), 2.23
(3H, s), 1.29 (3H, dd, J = 7.2, 7.2 Hz), 1.27 (3H, dd, J = 7.2, 7.2
Hz); 13C NMR (101 MHz, CDCl3) δ 13.8 (CH3), 20.6 (CH3), 64.0
(CH2), 81.5 (C), 128.8 (C), 130.9 (C), 156.6 (C), 162.7 (C), 169.8(C); IR (ATR, KBr) ν = 1690, 1761, 3299 cm−1; HRMS (ESI-TOF)
calcd for C16H15O7NF5 [M + H]+ 428.0763; found 428.0782.
Diethyl α-acetoxy-α-(acetylamino)malonate (5d).4 Yield 99%.
White solid, mp 96.4–96.7 °C. 1H NMR (400 MHz, CDCl3) δ
7.50 (1H, br s), 4.30 (4H, q, J = 7.2 Hz), 2.19 (3H, s), 2.07 (3H,s), 1.28 (6H, t, J = 7.2 Hz); 13C NMR (101 MHz, CDCl3) δ 13.8
(CH3), 20.9 (CH3), 22.8 (CH3), 63.6 (CH2), 81.8 (C), 163.5 (C),169.3 (C), 170.1 (C); IR (ATR, KBr) ν = 1694, 1765, 3359 cm−1;
HRMS (ESI-TOF) calcd for C11H18O7N [M + H]+ 276.1078;
found 276.1078.
Diethyl α-acetoxy-α-( propanoylamino)malonate (5e). Yield
quant. White solid, mp 67.1–67.7 °C. 1H NMR (400 MHz,CDCl3) δ 7.41 (1H, br s), 4.30 (4H, q, J = 7.2 Hz), 2.30 (2H, q, J =7.6 Hz), 2.27 (3H, s), 1.27 (6H, t, J = 7.2 Hz), 1.15 (3H, t, J = 7.6
Hz); 13C NMR (101 MHz, CDCl3) δ 9.1 (CH3), 13.9 (CH3), 20.9
(CH3), 29.0 (CH2), 63.6 (CH2), 81.8 (C), 163.6 (C), 170.2 (C),172.8 (C); IR (ATR, KBr) ν = 1698, 1765, 3284 cm−1; HRMS
(ESI-TOF) calcd for C12H21O7N [M + H]+ 290.1234; found290.1234.
Diethyl α-acetoxy-α-(butanoylamino)malonate (5f ). Yield
quant. White solid, mp 65.9–66.1 °C. 1H NMR (400 MHz,CDCl3) δ 7.42 (1H, br s), 4.30 (4H, q, J = 7.2 Hz), 2.24 (2H, t, J =7.6 Hz), 2.18 (3H, s), 1.66 (2H, tq, J = 7.6, 7.6 Hz), 1.27 (6H, t,
J = 7.2 Hz), 0.95 (3H, t, J = 7.6 Hz); 13C NMR (101 MHz, CDCl3)
δ 13.5 (CH3), 13.9 (CH3), 18.7 (CH2), 20.9 (CH3), 37.7 (CH2),
63.6 (CH2), 81.7 (C), 163.5 (C), 170.1 (C), 172.1 (C); IR (ATR,
KBr) ν = 1694, 1758, 3363 cm−1; HRMS (ESI-TOF) calcd for
C13H23O7N [M + H]+ 304.1399; found 304.1391.
Diethyl α-acetoxy-α-(dodecanoylamino)malonate (5g). Yield
quant. Brown solid, mp 58–59 °C. 1H NMR (400 MHz, CDCl3) δ
7.39 (1H, br s), 4.30 (4H, q, J = 7.2 Hz), 2.25 (2H, t, J = 7.6 Hz),2.17 (3H, s), 1.62 (2H, tt, J = 7.2, 7.2 Hz), 1.25–1.29 (22H, m),

2288 | Org. Biomol. Chem., 2022, 20, 2282–2292

Organic & Biomolecular Chemistry0.88 (3H, t, J = 6.8 Hz); 13C NMR (101 MHz, CDCl3) δ 13.8
(CH3), 14.1 (CH3), 20.8 (CH3), 22.7 (CH3), 25.1 (CH2), 29.0
(CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 29.6 (CH2), 31.9
(CH2), 35.9 (CH2), 63.5 (CH2), 81.7 (C), 163.5 (C), 170.1 (C),172.1 (C); IR (ATR, KBr) ν = 1756, 3363 cm−1; HRMS (ESI-TOF)
calcd for C21H37O7NNa [M + Na]+ 438.2462; found 438.2442.
Diethyl α-acetoxy-α-( pivaloylamino)malonate (5h). Yield
quant. White solid, mp 67.6–68.3 °C. 1H NMR (400 MHz,CDCl3) δ 7.62 (1H, br s), 4.31 (2H, dq, J = 7.2, 10.8 Hz), 4.27
(2H, dq, J = 7.2, 10.8 Hz), 2.18 (3H, s), 1.27 (6H, dd, J = 7.2, 7.2
Hz), 1.22 (9H, s); 13C NMR (101 MHz, CDCl3) δ 13.8 (CH3), 20.9
(CH3), 27.0 (CH3), 38.7 (C), 63.4 (CH2), 81.9 (C), 163.6 (C),170.1 (C), 177.4 (C); IR (ATR, KBr) ν = 1694, 1762, 3438 cm−1;
HRMS (ESI-TOF) calcd for C14H24O7N [M + H]+ 318.1547;
found 318.1555.
Diethyl α-acetoxy-α-[(trifluoroacetyl)amino]malonate (5i).
Yield 97%. White solid, mp 39.8–40.3 °C. 1H NMR (400 MHz,CDCl3) δ 8.21 (1H, br s), 4.36 (2H, dq, J = 7.2, 10.8 Hz), 4.31
(2H, dq, J = 7.2, 10.8 Hz), 2.21 (3H, s), 1.28 (6H, dd, J = 7.2, 7.2
Hz); 13C NMR (101 MHz, CDCl3) δ13.7 (CH3), 20.5 (CH3), 64.3
(CH2), 80.9 (C), 115.0 (q, JC–F = 286 Hz), 156.0 (q, JC–F = 39 Hz),162.2 (C), 169.6 (C); IR (ATR, KBr) ν = 1753 (br), 3327 cm−1;
HRMS (ESI-TOF) calcd for C11H14O7N1F3Na [M + Na]+
352.0615; found 352.0624.
Diethyl α-acetoxy-α-[(tert-butoxycarbonyl)amino]malonate(5j). Yield 93%. Colorless oil. 1H NMR (400 MHz, CDCl3)
δ 6.63 (1H, br s), 4.36–4.23 (4H, m), 2.19 (3H, s), 1.272 (3H, dd,
J = 7.2, 7.2 Hz), 1.268 (3H, dd, J = 7.2, 7.2 Hz); 13C NMR(101 MHz, CDCl3) δ 13.8 (CH3), 21.0 (CH3), 28.1 (CH3), 30.9(C), 63.4 (CH2), 83.0 (C), 153.0 (C), 163.5 (C), 170.0 (C); IR(ATR, KBr) ν = 1762 (br), 3426 cm−1; HRMS (ESI-TOF) calcd for
C14H24O8N [M + H]+ 334.1496; found 334.1491.
Diethyl α-acetoxy-α-[1-acetyl-L-prolylamino]malonate (5l).
Yield 88%. Colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.71 (brs, 1H), 4.57 (dd, J = 8.2, 2.5 Hz, 1H), 4.45–4.06 (m, 4H) (ddd, J= 7.2, 2.5 Hz, 2H), 3.56 (ddd, J = 9.3, 7.9, 3.4 Hz, 1H), 3.44
(ddd, J = 9.3, 9.3, 7.1 Hz, 1H), 2.30 (ddd, J = 9.3, 6.3, 3.4 Hz,
1H), 2.16 (s, 3H), 2.11 (s, 3H), 2.09–1.83 (m, 3H), 1.26 (td, J =7.2, 2.5 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.0 (C), 170.9(C), 169.8 (C), 163.6 (C), 82.2 (C), 63.50 (CH2), 63.47 (CH2), 59.5
(CH3), 48.2 (CH2), 27.6 (CH2), 25.1 (CH2), 22.4 (CH3), 21.0
(CH3), 14.0 (CH3), 14.0 (CH3); IR (ATR, KBr) ν = 1762 (br),3426 cm−1; HRMS (ESI-TOF) calcd for C14H24O8N [M + H]+
334.1496; found 334.1491.

General procedure for synthesis of double adduct 6
In a screw capped test-tube, a toluene solution (3 mL) of N,Oacetal 5a (140 mg, 0.4 mmol), triethylamine (84 μL, 0.6 mmol),and 1-methylindole (63 mg, 0.48 mmol) was heated at 120 °C
for 3 h. The resultant solution was poured into chloroform(50 mL), and 12 M hydrochloric acid (1 mL, 12 mmol) was
added, then, washed with water (50 mL × 2). The organic layer
was dried over magnesium sulfate and concentrated. The
residue was washed with hexane (100 mL) to aﬀord double
adduct 11a (169 mg, 0.4 mmol, yield quant.) as a white solid.

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Further purification was performed by recrystallization frommixed solvent (Et2O–hexane).
The experimental procedure were conducted in the sameway for the synthesis of other double adducts 6–12.
Diethyl α-[(4-methylbenzoyl)amino]-α-(1-methylindol-3-yl)
malonate (11a). Yield 97%. Colorless plates (from Et2O–
hexane), mp 124.2–124.9 °C. 1H NMR (400 MHz, CDCl3) δ 8.01
(1H, br s), 7.76 (1H, s), 7.73 (2H, d, J = 8.0 Hz), 7.66 (1H, d, J =8.0 Hz), 7.27 (1H, d, J = 8.0 Hz), 7.23 (2H, d, J = 8.0 Hz), 7.18
(1H, ddd, J = 8.0, 6.8, 1.2 Hz), 7.07 (1H, ddd, J = 8.0, 6.8, 1.2
Hz), 4.34 (2H, dq, J = 6.8, 10.8 Hz), 4.24 (2H, dq, J = 6.8, 10.8
Hz), 3.76 (3H, s), 2.39 (3H, s), 1.24 (6H, dd, J = 6.8, 6.8 Hz); 13C
NMR (101 MHz, CDCl3) δ 14.0 (CH3), 21.5 (CH3), 33.0 (CH3),
62.8 (CH2), 65.1 (C), 108.2 (C), 109.5 (CH), 119.5 (CH), 120.0(CH), 121.4 (CH), 125.8 (C), 127.2 (CH), 129.2 (CH), 130.5 (CH),130.8 (C), 137.0 (C), 142.3 (C), 165.6 (C), 167.9 (C); IR (ATR,
KBr) ν = 1670, 1738, 3418 cm−1; HRMS (ESI-TOF) calcd for
C24H26O5N2Na [M + Na]+ 446.1812; found 446.1802.
Diethyl α-[(4-methylbenzoyl)amino]-α-(1H-pyrrol-2-yl)malonate (6a). Yield 88%. Yellow oil. 1H NMR (400 MHz, CDCl3) δ
9.8–9.7 (1H, br), 7.92 (1H, br s), 7.72 (2H, d, J = 8.0 Hz), 7.25
(2H, d, J = 8.0 Hz), 6.79 (1H, ddd, J = 0.8, 2.8, 2.8 Hz), 6.10 (1H,
ddd, J = 2.8, 2.8, 3.2 Hz), 6.02 (1H, ddd, J = 1.6, 2.8, 2.8 Hz),4.37 (2H, dq, J = 7.2, 10.8 Hz), 4.32 (2H, dq, J = 7.2, 10.8 Hz),2.40 (s, 3H), 1.29 (6H, dd, J = 7.2, 7.2 Hz); 13C NMR (101 MHz,CDCl3) δ 14.0 (CH3), 21.5 (CH3), 63.2 (CH2), 65.3 (C), 107.2(CH), 107.3 (CH), 118.9 (CH), 126.9 (C), 127.3 (CH), 129.3 (CH),
130.1 (C), 142.8 (C), 166.9 (C) 167.0 (C); IR (ATR, KBr) ν = 1658,
1741, 3414 cm−1; HRMS (ESI-TOF) calcd for C19H23O5N2 [M +H]+ 359.1602; found 359.1608.
Diethylα-(5-ethyl-1H-pyrrol-2-yl)-α-[(4-methylbenzoyl)
amino]malonate (7a). Yield quant. Yellow solid, mp
125.8–126.4 °C. 1H NMR (400 MHz, CDCl3) δ 9.5–9.3 (1H, br),7.89 (1H, br s), 7.71 (2H, d, J = 8.0 Hz), 7.25 (2H, d, J = 8.0 Hz),5.89 (1H, dd, J = 2.8, 3.2 Hz), 5.79 (1H, ddd, J = 0.8, 2.8, 3.2 Hz),4.35 (4H, q, J = 7.2 Hz), 2.62 (2H, q, J = 7.6 Hz), 2.40 (3H, s), 1.29
(6H, t, J = 7.2 Hz), 1.22 (3H, t, J = 7.6 Hz); 13C NMR (101 MHz,CDCl3) δ 13.3 (CH3), 14.0 (CH3), 20.9 (CH2), 21.5 (CH3), 63.1
(CH2) 65.1 (C), 103.4 (CH), 107.3 (CH), 125.1 (C), 127.3 (CH),
129.3 (CH), 130.3 (C), 135.5 (C), 142.7 (C), 166.8 (C) 167.1 (C); IR(ATR, KBr) ν = 1662, 1742, 3406 cm−1; HRMS (ESI-TOF) calcd for
C21H27O5N2 [M + H]+ 387.1915; found 387.1911.
Diethylα-[(4-methylbenzoyl)amino]-α-(3,5-dimethyl-1Hpyrrol-2-yl)malonate (8a). Yield quant. Yellow oil. 1H NMR(400 MHz, CDCl3) δ 9.7–9.6 (1H, br), 7.95 (1H, br s), 7.71 (2H,d, J = 8.0 Hz), 7.23 (2H, d, J = 8.0 Hz), 5.58 (1H, d, J = 2.8 Hz),4.35 (2H, dq, J = 7.2, 10.8 Hz), 4.24 (2H, dq, J = 7.2, 10.8 Hz),2.39 (3H, s), 2.21 (3H, s), 1.93 (3H, s), 1.24 (6H, dd, J = 7.2, 7.2
Hz); 13C NMR (101 MHz, CDCl3) δ 11.8 (CH3), 13.0 (CH3), 13.9
(CH3), 21.5 (CH3), 63.0 (CH2), 63.7 (C), 108.9 (CH), 116.8 (C),118.9 (C), 126.6 (C), 127.2 (CH), 129.3 (CH), 130.3 (C), 142.5(C), 165.8 (C) 167.3 (C); IR (ATR, KBr) ν = 1662, 1733,
3423 cm−1; HRMS (ESI-TOF) calcd for C21H22O5N2H [M + H]+
387.1915; found 387.1924.
Diethyl α-(4-ethyl-3,5-dimethyl-1H-pyrrol-2-yl)-α-[(4-methylbenzoyl)amino]malonate (9a). Yield quant. Yellow oil. 1H NMRThis journal is © The Royal Society of Chemistry 2022

Paper(400 MHz, CDCl3) δ 9.4–9.3 (1H, br), 7.93 (1H, br s), 7.62 (2H,d, J = 8.0 Hz), 7.18 (2H, d, J = 8.0 Hz), 4.17 (2H, dq, J = 7.2, 10.8
Hz), 4.11 (2H, dq, J = 7.2, 10.8 Hz), 2.27 (3H, s), 2.20 (2H, q, J =7.2 Hz), 2.04 (3H, s), 1.78 (3H, s), 1.09 (6H, dd, J = 7.2, 7.2 Hz),0.87 (3H, t, J = 7.2 Hz); 13C NMR (101 MHz, CDCl3) δ 9.93
(CH3), 11.2 (CH3), 14.3 (CH3), 16.1 (CH3), 17.9 (CH2), 21.6
(CH3), 63.9 (CH2), 65.2 (C), 116.3 (C), 119.0 (C), 121.8 (C), 123.5(C), 128.2 (CH), 130.3 (CH), 131.3 (C), 143.8 (C), 166.5 (C) 168.2(C); IR (ATR, KBr) ν = 1666, 1733, 3423 cm−1; HRMS (ESI-TOF)
calcd for C23H31O5N2 [M + H]+ 415.2228; found 415.2237.
Diethyl α-(1H-indole-3-yl)-α-[(4-methylbenzoyl)amino]malonate (10a). Yield 72%. Brown oil. 1H NMR (400 MHz, CDCl3)
8.63 (br s, 1H), 8.05 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.72–7.68(m, 1H), 7.69–7.62 (m, 1H), 7.24 (d, J = 8.2 Hz, 2H), 7.21–7.17(m, 1H), 7.11–6.99 (m, 2H), 4.35 (dq, J = 10.7, 7.1 Hz, 2H), 4.25
(dq, J = 10.6, 7.1 Hz, 2H), 2.40 (s, 3H), 1.23 (dd, J = 7.1, 7.1 Hz,
6H); 13C NMR (101 MHz, CDCl3) δ 167.9 (C), 166.0 (C), 142.5(C), 136.4 (C), 130.8 (C), 129.4 (CH), 127.4 (CH), 126.3 (CH),
125.2 (C), 121.8 (CH), 120.0 (CH), 119.8 (CH), 111.7 (CH), 109.5(C), 65.3 (C), 62.9 (CH2), 21.6 (CH3), 14.1 (CH3); HRMS
(ESI-TOF) calcd for C23H24O5N2Na [M + Na]+ 431.1577; found431.1588.
Diethyl α-[(4-methylbenzoyl)amino]-α-(1H-5-methylindol-3yl)malonate (12a). Yield 65%. White solid, mp 137.1–141.4 °C.
1
H NMR (400 MHz, CDCl3) δ 8.35 (1H, br), 7.99 (1H, br s), 7.75
(2H, d, J = 8.0 Hz), 7.73 (1H, d, J = 2.0 Hz), 7.44 (1H, d, J = 0.8
Hz), 7.24 (2H, d, J = 8.0 Hz), 7.16 (1H, d, J = 8.0 Hz), 6.93 (1H,
dd, J = 8.0, 2.0 Hz), 4.35 (2H, dq, J = 10.8, 7.2 Hz), 4.26 (2H, dq,
J = 10.8, 7.2 Hz), 2.41 (3H, s), 2.39 (3H, s), 1.34 (6H, dd, 7.2, 7.2
Hz); 13C NMR (101 MHz, CDCl3) δ 167.9 (C), 165.9 (C), 142.5(C), 134.7 (C), 130.9 (C), 129.4 (CH), 129.0 (C), 127.4 (CH),
126.3 (CH), 125.5 (C), 123.5 (CH), 119.7 (CH), 111.2 (CH), 109.3(C), 65.3 (C), 62.9 (CH2), 21.8 (CH3), 21.6 (CH3), 14.1 (CH3);
HRMS (ESI-TOF) calcd for C24H26O5N2 [M + H]+ 423.1915;
found 423.1905.
Diethyl α-[(trifluoroacetyl)amino]-α-(1H-pyrrol-2-yl)malonate(6i). Yield 85%. Colorless plates (from Et2O–hexane), mp
78.1–78.3 °C. 1H NMR (400 MHz, CDCl3) δ 9.6–9.4 (1H, br),8.10 (1H, br s), 6.82–6.84 (1H, m), 6.13 (1H, ddd, J = 2.8, 6.0
Hz), 6.02–6.03 (1H, m), 4.37 (2H, dq, J = 7.2, 10.8 Hz), 4.31
(2H, dq, J = 7.2, 10.8 Hz), 1.28 (6H, dd, J = 7.2, 7.2 Hz); 13C
NMR (101 MHz, CDCl3) δ 13.8 (CH3), 63.9 (CH2), 64.2 (C),108.0 (CH), 108.0 (CH), 115.4 (q, JC–F = 285 Hz), 119.7 (CH),
124.0 (C), 156.6 (q, JC–F = 39 Hz) 165.6 (C); IR (ATR, KBr) ν =1738 (br), 3395 cm−1; HRMS (ESI-TOF) calcd for C13H16O5N2F3[M + H]+ 337.1006; found 337.1010.
Diethylα-[(trifluoroacetyl)amino]-α-(1H-indole-3-yl)malonate (10i). Yield 52%. Colorless plates (from Et2O–hexane), mp
112.1–112.9 °C. 1H NMR (400 MHz, CDCl3) δ 8.5–8.4 (1H, br),
8.22 (1H, br s), 7.73 (1H, d, J = 2.8 Hz), 7.52 (1H, d, J = 8.0 Hz),7.28 (1H, d, J = 8.0 Hz), 7.16 (1H, dd, J = 8.0, 8.0 Hz), 7.10 (1H,
dd, J = 8.0, 8.0 Hz), 4.37 (2H, dq, J = 7.2, 10.8 Hz), 4.31 (2H, dq,
J = 7.2, 10.8 Hz), 1.23 (6H, dd, J = 7.2, 7.2 Hz); 13C NMR(101 MHz, CDCl3) δ 13.8 (CH3), 63.9 (CH2), 64.7 (C), 108.0 (C),111.7 (CH), 115.4 (q, JC–F = 250 Hz), 119.7 (CH), 120.3 (CH),122,3 (CH), 124.6 (C), 126.3 (CH), 136.1 (C), 156.6 (q, JC–F = 37

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PaperHz), 165.6 (C); IR (ATR, KBr) ν = 1734, 1766, 3390 cm−1; HRMS
(ESI-TOF) calcd for C17H18O5N2F3 [M + H]+ 387.1162; found387.1154.
Diethyl α-[(trifluoroacetyl)amino]-α-(1-methylindol-3-yl)malonate (11i). Yield 83%. Brown oil. The purity of the productwas improved by short column chromatography on silica gel(after elution of 1-methylindole with chloroform–hexane (1/1),
eluted with ethyl acetate), but further purification was notpossible. 1H NMR (400 MHz, CDCl3) δ 8.21 (1H, br s), 7.73
(1H, s), 7.51 (1H, ddd, J = 0.8, 1.2, 8.0 Hz), 7.30 (1H, ddd, J =0.8, 1.2, 8.0 Hz), 7.22 (1H, ddd, J = 1.2, 8.0, 8.0 Hz), 7.10 (1H,
ddd, J = 1.2, 8.0, 8.0 Hz), 4.39–4.21 (4H, m,), 3.76 (3H, s), 1.23
(6H, dd, J = 7.2, 7.2 Hz); 13C NMR (101 MHz, CDCl3) δ 13.8
(CH3), 33.1 (CH3), 63.5 (CH2), 65.1 (C), 106.0 (C), 109.8 (CH),
115.4 (q, JC–F = 286 Hz), 119.2 (CH), 120.0 (CH), 121,9 (CH),
125.4 (C), 130.7 (CH), 136.8 (C), 156.3 (q, JC–F = 38 Hz) 166.3(C); IR (ATR, KBr) ν = 1733 (br), 3386 cm−1; HRMS (ESI-TOF)
calcd for C18H20O5N2F3 [M + H]+ 401.1319; found 401.1316.
Diethylα-(tert-butylcarboxyamino)-α-(1-methylindol-3-yl)
malonate (11j). Yield 83%. White solid, 127.9–128.6 °C. 1H
NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 1H), 7.64 (s, 1H),
7.28 (d, J = 8.2 Hz, 1H), 7.19 (dd, J = 8.2, 8.2 Hz, 1H), 7.08 (dd,J = 8.2, 8.2 Hz, 1H), 6.44 (s, 1H), 4.48–4.24 (m, 3H), 4.20 (dq, J= 10.7, 7.1 Hz, 2H), 3.77 (s, 3H), 1.39 (br s, 9H), 1.24 (dd, J =7.1 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 168.0 (C), 154.0 (C),137.1 (C), 129.9 (CH), 126.0 (C), 121.6 (CH), 120.6 (CH), 119.5(CH), 109.4 (CH), 109.0 (C), 80.3 (C), 65.3 (C), 62.7 (CH2), 33.1
(CH3), 28.3 (CH3), 14.1 (CH3); HRMS (ESI-TOF) calcd for
C21H28N2O6Na [M + Na]+ 427.1840; found 427.1843.
Diethyl α-(1-acetyl-L-prolylamino)-α-(1-methylindol-3-yl)malonate (11l). Yield 75%. Brown oil. The purity of the productwas improved by short column chromatography on silica gel(after elution of 1-methylindole with chloroform–hexane (1/1),
eluted with ethyl acetate), but further purification was notpossible. 1H NMR (400 MHz, CDCl3) δ 8.60 (1H, br s), 7.7 (1H,s), 7.68 (1H, d, J = 8.0 Hz), 7.25 (1H, d, J = 8.0 Hz), 7.18 (1H,
ddd, J = 8.0, 6.8, 1.2 Hz), 7.07 (1H, ddd, J = 8.0, 6.8, 1.2 Hz),4.58 (1H, dd, J = 7.6, 7.6 Hz), 4.34–4.24 (4H, m),3.74 (3H, s)
3.59–3.54 (1H, m), 3.48–3.42 (1H, m), 2.33–1.91 (1H, m), 2.14
(3H, s), 2.00–1.91 (3H, m), 1.29–1.21 (6H, m); 13C NMR(100 MHz, CDCl3) δ 170.8 (C), 169.9 (C), 167.5 (C), 167.4 (C),137.2 (C), 130.1 (CH), 125.9 (C), 121.3 (CH), 120.9 (CH), 119.1(CH), 109.3 (CH), 108.3 (C), 65.3 (C), 62.6 (CH2), 62.5 (CH2),
59.4 (CH), 48.2 (CH2), 33.0 (CH3), 27.5 (CH2), 24.8 (CH2), 22.5
(CH3), 14.0 (CH3); IR (ATR, KBr) ν = 1701, 1757, 3255 cm−1;
HRMS (ESI-TOF) calcd for C23H29O6N3 [M + H]+ 444.2129;
found 444.2121.
General procedure for hydrolysis and decarboxylation of 11a
To a solution of double adduct 11a (21 mg, 0.05 mmol) in THF(2 mL), potassium tert-butoxide (11 mg, 0.10 mmol) was
added, and the resultant mixture was stirred at room temperature overnight. After evaporation, the residue was dissolved inchloroform (20 mL), and 12 M hydrochloric acid (1 mL,
12 mmol) was added, then, washed with water (10 mL). The
organic layer was dried over magnesium sulfate and concen-

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Organic & Biomolecular Chemistry
trated. The residue was washed with hexane (100 mL) to aﬀord
amino acid derivative 16a (14 mg, 0.044 mmol, yield 88%) as awhite solid.
The decarboxylation of other double adducts were also performed by the same experimental procedure.
2-[(4-Methylbenzoyl)amino]-2-(1-methylindol-3-yl)ethanoic
acid (16a). Yield 98%. White solid. 1H NMR (400 MHz, DMSOd6) δ 8.74 (1H, d, J = 7.2 Hz), 7.82 (2H, d, J = 8.0 Hz), 7.63 (1H,d, J = 7.2 Hz), 7.43 (1H, d, J = 8.0 Hz), 7.42 (1H, s), 7.23 (2H, d,
J = 8,0 Hz), 7.18 (1H, dd, J = 7.2, 7.2 Hz), 7.06 (1H, dd, J = 7.2,
7.2 Hz), 5.80 (1H, d, J = 7.2 Hz), 3.80 (3H, s), 2.35 (3H, s), 13C
NMR (100 MHz, CDCl3) δ 20.9 (CH3), 32.4 (CH3), 49.6 (CH),109.1 (C), 109.8 (CH), 119.0 (CH), 121.4 (CH), 126.5 (C), 127.7(CH), 127.5 (CH), 128.6 (CH), 128.7 (CH), 131.0 (C), 136.5 (C),141.2 (C), 166.1 (C), 172.3 (C); HRMS (ESI-TOF) calcd for
C19H18O3N2 [M + H]+ 323.1390; found 323.1396.
2-(1-Methylindol-3-yl)-2-( pivaloylamino)ethanoic acid (16h).
Yield 71%. Yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.67 (1H,d, J = 8.0 Hz), 7.25 (1H, d, J = 8.0 Hz), 7.19 (1H, dd, J = 7.2, 7.2
Hz), 7.12 (1H, s), 7.06 (1H, dd, J = 7.2, 7.2 Hz), 6.71 (1H, d, J =7.2 Hz), 5.71 (1H, d, J = 6.4 Hz), 3.66 (3H, s), 1.16 (9H, s); 13C
NMR (100 MHz, CDCl3) δ 27.1 (CH3), 32.7 (CH3), 38.6 (C), 50.5
(CH), 109.4 (CH), 110.3 (C), 119.4 (CH), 119.5 (CH), 121.8 (CH),
126.3 (C), 128.5 (CH), 137.1 (C), 174.5 (C), 178.2 (C); IR (ATR,
KBr) ν = 1718 cm−1; HRMS (ESI-TOF) calcd for C16H19O3N2[M + Na]+ 311.1366; found 311.1382.
2-(1-Methylindol-3-yl)-2-(trifluoroacetylamino)ethanoic acid(16i). Yield 98%. White solid. 1H NMR (400 MHz, CDCl3) δ
7.64 (1H, d, J = 8.0 Hz), 7.82 (2H, d, J = 8.0 Hz), 7.33 (1H, dd,
J = 7.2, 7.2 Hz), 7.28 (1H, d, J = 7.2, 7.2 Hz), 7.18 (1H, dd, J =7.2, 7.2 Hz), 7.12 (1H, m), 5.87 (1H, d, J = 6.8 Hz), 3.79 (3H, s).
2-(tert-Butylcarboxyamino)-2-(1-methylindol-3-yl)ethanoic acid(16j). Yield quant., yellow oil.1H NMR (400 MHz, CD3CN)
δ 7.62 (1H, d, J = 8.0 Hz), 7.39 (1H, d, J = 8.0 Hz) 7.23 (1H, dd, J= 8.0, 8.0 Hz), 7.21 (1H, s), 7.11 (1H, dd, J = 8.0, 8.0 Hz), 5.92
(1H, br s), 5.42 (1H, d, J = 3.2 Hz), 3.76 (3H, s), 1.42 (9H, s). 13C
NMR (101 MHz, CD3CN) δ 173.2 (C), 156.4 (C), 138.0 (C), 129.4(CH), 127.1 (C), 122.9 (CH), 120.4 (CH), 120.0 (CH), 110.8 (CH),110.3 (CH), 80.1 (C), 51.5 (CH), 33.2 (CH3), 28.5 (CH3); HRMS
(ESI-TOF) calcd for C16H19O4N2 [M − H]− 303.1350; found303.1342.
2-(1-Acetyl-L-prolylamino)-2-(1-methylindol-3-yl)ethanoic acid(16l). Although a mixture of four isomers was obtained, major
isomer could be isolated by reprecipitation from ethyl acetate.
White solid, mp 174.8 °C (decomp.). 1H NMR (400 MHz,DMSO-d6) δ 8.72 (1H, d, J = 6.4 Hz), 8.37 (1H, d, J = 7.6 Hz),7.58 (2H, d, J = 7.6 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.42 (1H, d, J =8.0 Hz), 7.36 (1H, s), 7.29 (1H, s), 7.19 (1H, dd, 8.0, 8.0 Hz),7.17 (1H, dd, 8.0, 8.0 Hz), 7.07 (1H, dd, 8.0, 8.0 Hz), 7.05 (1H,
dd, 8.0, 8.0 Hz), 5.56 (1H, d, 7.6 Hz), 5.48 (1H, d, 6.4 Hz), 4.45
(1H, dd, 8.4, 2.1 Hz), 4.41 (1H, dd, 8.0, 2.4 Hz), 3.78 (3H, s),
3.76 (3H, s), 2.19–2.08 (1H, m), 1.98 (3H, s), 1.90 (3H, s),
2.00–1.68 (9H, m),13C NMR (100 MHz, DMSO-d6) δ 22.1 (CH3),
22.4 (CH3), 22.7 (CH2), 24.2 (CH2), 29.5 (CH2), 31.9 (CH2),
32.48 (CH3), 32.50 (CH3) 46.4 (CH2), 47.6 (CH2), 49.2 (CH3),
49.6 (CH3), 58.9 (CH), 59.6 (CH), 108.6 (C), 109.8 (C), 109.9

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Organic & Biomolecular Chemistry(CH), 110.0 (CH), 119.1 (CH), 119.1 (CH), 119.15 (CH), 119.24(CH), 121.6 (CH), 121.7 (CH), 126.1 (C), 126.2 (C), 128.2 (CH),
128.7 (CH), 136.7 (C), 136.7 (C), 168.7 (C), 168.8 (C), 171.4 (C),172.1 (C), 172.1 (C), 172.2 (C); HRMS (ESI-TOF) calcd for
C18H21N3O4Na [M + Na]+ 366.1424; found 366.1423.

Author contributions
Asahara and Nishiwaki came up with the idea for this study
and were the main driving force behind it. Bonkohara, Takagi,
and Iwai performed experiments. Iwai and Ito conducted X-ray
crystallography and DFT calculations. Yoshioka, Tani, andUmezu supplied DEMO and discussed on the Experimental
results.

Conﬂicts of interest
There are no conflicts to declare.

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